The present invention relates to therapeutic methods for modulating cellular immunity by administering to an animal or cells from an animal, small molecules that affect the expression of cytokines, activate T cells, and stimulate T cell proliferation.
Cytokines are secreted regulatory proteins that control the survival, growth, differentiation and effector function of immune cells. Cytokines encompass those families of regulators variously known as growth factors, colony-stimulating factors, interleukins, lymphokines, monokines, and interferons. They are molecules found in the extracellular medium that interact with specific target cells to communicate information regarding the status of the animal and they result in an appropriate biological response in the target tissue. The producer cells therefore, represent the biological sensors of the animals"" condition; the cytokines represent, the method of signal transduction; the receptors represent the means of signal reception; and the responsive cells represent the means of effecting an appropriate biological response. There appear to be very few biological responses that are mediated by only one cytokine and many responses that can be achieved by several different cytokines especially when they are used in combination. Gene deletion experiments reveal that few individual cytokines are absolutely essential for life or even for individual cellular functions.
The key feature of cytokines compared to classical hormones is that they are rarely found in the circulation but rather are produced by cells that are widespread in the body. Cytokines may act in an autocrine, paracrine, or intercrine manner. Cytokine producer cells are often physically located immediately adjacent to the responder cells and they generally secrete very small quantities of cytokine with which the responder cells interact. The responder cells deplete the cytokine they respond to in the process of receptor mediated endocytosis. Many cytokines bind to elements of the extracellular matrix around responder cells further restricting their spread beyond the immediate site and increasing their bioavailability to the responder cells. An extreme example of this bound localization are the cell surface cytokines, such as TNF alpha, which presumably require cell-cell contact for their action. Finally, there are several examples of high levels of circulating soluble cytokine receptors, binding proteins and even receptor antagonists which may serve to inhibit the biological action of a cytokine that does find its way into the serum. Cytokines have very stable structures; most cytokines are relatively small proteins that contain protective carbohydrate and intramolecular disulphide bonds. These elements enhance the solubility, stability, and protease resistance of the cytokines.
Among cytokine producers are T helper (Th) cells which can be divided into two functional subsets, Th1 and Th2, which can be distinguished by the patterns of cytokines they secrete. Th1 cells secrete interleukin (IL)-2, interferon (IFN)-gamma, TNF alpha and beta, and lymphotoxin, among others, and are responsible for the development of the cell-mediated immune response, often called delayed-type hypersensitivity (DTH). This response is critical for the successful removal of intracellular pathogens, such as certain bacteria and viruses. Th2 cells secrete IL-4, IL-5, IL-10, and IL-13 and are responsible for the development of high levels of IgG1, IgA, and IgE production by B cells, and for the activation of effector cells such as eosinophils. Responder cells that respond by producing antibodies are included in class called B-cells.
The commitment to a Th1 or Th2 phenotype appears to occur within the first 48 hours after antigenic stimulation, and is characterized by changes in the expression of particular cell surface markers and cell signaling components. There often exists a relatively large population of activated T cells that represent uncommitted precursors which can become either Th1 or Th2 cells. An area of considerable research has been the study of the role of cytokines in Th1 and Th2 differentiation, which is thought by some to be the most critical factor in determining the nature of the immune response.
Perhaps the most important determinant for the development of stable Th1 and Th2 cells is the cytokine milieu present at the time of initial priming, as well as during the course of a recall response. It has been reported that Th2 cells can be induced by IL-12 to secrete IFN-gamma. Paul, William E., Fundamental Immunology, Fourth Edition, Pub. Lippincott-Raven, 897 (1999). Therefore, a method of increasing Th1 cytokines and/or decreasing Th2 cytokines, to generate a polarized Th1 response has clinical significance in stimulating and maintaining cellular immunity.
Accordingly, it is an object of this invention to provide a method to elicit, enhance or maintain a polarized Th1 response in an animal by administering small molecules such as beta-alethine (BETATHINE(trademark) also Beta LT(trademark) and BT), beta-alanyl taurine, carbobenzoxy beta-alanyl taurine (Taurox(trademark)-SB, hereinafter Taurox-SB), and various other aminothiols and amino phosphates. It is another object to provide therapeutic methods that modulate cellular immunity, manipulate cytokine expression, activate T cells, and induce T cell proliferation in order to prevent and treat certain diseases responsive to such therapies. It is a further object to provide pharmaceutical compositions to treat pathogen-induced infections.
It is an object of the invention to provide a method for biasing the immune system toward producing, enhancing or maintaining a polarized Th1 response in an animal. It is another object of the invention to provide a method of preventing or treating diseases that respond to an increase in one or more Th1 cytokines. It is also a specific object to provide a method of producing, enhancing or maintaining cellular immunity by administering one or more compounds of Formula I as defined in this application. It is a further object to provide a method of activating T cells, stimulating or increasing T cell proliferation, increasing or stimulating T cell-dependent cytotoxicity and increasing the production of cytotoxic T lymphocytes in an animal.
It is a further object of the present invention to provide a method of preventing or treating pathogen-induced infections by administering to an animal a combination of one or more compounds of Formula I as defined in the following section, and one or more antimicrobial agents such as antibiotics, antiviral agents, or antifungal agents. It is a further object to provide a pharmaceutical composition for treating or preventing pathogen-induced infections by administering to an animal a combination of one or more compounds of Formula I as defined in the following section, and one or more antimicrobial agents.
It is another object of the present invention to provide a method ti prevent or treat ischemia or reperfusion injuries in an animal by administering one or more compounds of Formula I. Finally, it is yet another object to provide a method and a pharmaceutical composition to decrease soluble TNF in an animal.
Another aspect of the present invention is to provide a set of compounds that modulate the immune response causing a coordinated increase or decrease in various cytokines and other signaling molecules to obtain a desired effect. It is an aspect to cause an increase in pro-inflammatory cytokines in unstimulated cells needing to produce more cytokines but a decrease in several signalling agents in cells that are previously overstimulated. It is another object to provide a method of modulating the immune system toward or away from producing, enhancing or maintaining a polarized Th1 response in an animal, and methods for increasing or decreasing cellular immunity in an animal